Project Summary Sudden cardiac arrest (SCA) continues to be a major public health concern, accounting for up to 400,000 annual deaths in the US alone. In Western populations, ventricular fibrillation is the most common electrophysiologic mechanism for SCA while coronary artery disease (CAD) is the most common underlying disease. Despite recent advances in treatment and prevention of CAD, SCA continues to be one of the leading causes of mortality. There are few effective approaches to SCA prevention for the general population. Identifying those at increased risk, and discovering novel therapeutic targets for arrhythmia prevention and treatment is of great public health importance. Hydrogen sulfide, H2S, is a toxic environmental pollutant that has recently emerged as an important physiological signaling molecule. H2S is one of three identified gasotransmitters (along with NO and CO) with significant biological roles in various tissues to maintain proper function. H2S is recognized as a cardioprotective substrate that preserves cardiomyocyte function and prevents toxicity. Most relevant to this application, H2S has electrophysiological significance in regulating L-type Ca2+, Na+ and ATP dependent K+ (KATP) channels that maintain a normal QT-period and reduce the prolonged QT period following ischemia reperfusion injury in various animal models. H2S also protects against ventricular tachyarrhythmia during cardiac hypertrophy and ischemia/reperfusion injury. Inhibition of the major enzyme responsible for H2S biosynthesis in cardiac tissue leads to reduced H2S levels in both cardiac tissue as well as circulating plasma, and results in cardiac injury. This research project will test the hypothesis that higher circulating H2S concentrations are associated with lower risk of SCA. Aim 1 will examine the risk associated with SCA and circulating H2S in plasma and RBC membranes in two large population-based studies of SCA. Aim 2 will test the role of H2S regulation in adult human cardiomyocyte dysfunction during hypoxic stress and for the first time, determine the genomic pathways associated with cardiac homeostasis of H2S to identify new pathways involved in the synthesis and especially metabolism of H2S under hypoxic stress. The two aims together will aid in developing new clinical strategies to combat SCA, improve risk stratification and identify novel H2S related drug targets for better treatment and prevention.